study of efficacy of oral sacubitril/valsartan in adult patients with non-obstructive hypertrophic cardiomyopathy

Conditions: Cardiomyopathy, Hypertrophic

Summary: the purpose of this study was to determine if lcz696 can improve functional capacity (via improved peak vo2) in non-obstructive hypertrophic cardiomyopathy (hcm) patient population over the course of 50 weeks of treatment.

this was a multi-center, placebo-controlled, patient and investigator-blinded study in non-obstructive hcm patients. the study comprised a ≤ 35-day screening/baseline period, a 4-week single-blind treatment run-in period, followed by a 46-week double-blind placebo-controlled treatment period (total treatment period of 50 weeks), and a follow-up period approximately 30 days after the last dose. the treatment run-in period was planned to ensure that as large a proportion as possible of patients: 1. had stable symptoms and could comply with study visits, and 2. could tolerate at least low dose lcz696. during the run-in period, all patients received oral (p.o.) placebo b.i.d. for 2 weeks followed by 50 mg p.o. of active lcz696 b.i.d. for 2 weeks. patients who were unable to tolerate either placebo or the 50 mg p.o. b.i.d. dose level, were considered treatment run-in failures and were neither randomized into the double-blind, placebo-controlled study, nor included in the efficacy analysis. in the double-blind treatment period, participants were randomized 1:1 to placebo or lcz696. in the lcz696 arm, participants started at a lcz696 100 mg p.o. b.i.d dose. after approximately 14 days, patients who tolerated the 100 mg p.o. b.i.d. dose were up-titrated to 200 mg p.o. b.i.d. dose, whereas those who did not meet the safety criteria were titrated back down to the 50 mg b.i.d. dose.

Eligibility criteria:
inclusion criteria: * diagnosed with hypertrophic cardiomyopathy with a left ventricular wall thickness greater than or equal to 13mm as determined by the echocardiogram obtained during the screening/baseline period * left ventricular ejection fraction (lvef) greater than or equal to 50% as determined by echocardiogram obtained during the screening/baseline period * symptoms consistent with new york heart association (nyha) class ii-iii heart failure by physician assessment, or asymptomatic/nyha class i patients with: * nt-probnp blood sample levels above 250 pg/ml and * peak vo2 of less than or equal to 80% of predicted based on age and gender as determined by cardiopulmonary exercise testing exclusion criteria: * women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for ≥7 days after stopping study drug * patients with a resting or provokable left ventricular outflow tract gradient of greater than or equal to 30mm hg * septal reduction procedure within 3 months of the screening/baseline visit * history of atrial fibrillation within 6 months of the screening/baseline visit or placement of icd for secondary prevention * patients with a peak vo2 on the screening/baseline cardiopulmonary exercise test of \> 80% of predicted based on age and gender * patients who require treatment with ace inhibitors, angiotensin receptor blockers (arbs), or renin inhibitors * known infiltrative or storage disorder such as fabry disease, or amyloidosis * known or suspected symptomatic coronary artery diseases or evidence of prior myocardial infarction * systolic blood pressure of \<100 mmhg or symptomatic hypotension during the screening/baseline period or treatment run-in period * contraindication to arb administration or prior history of angioedema * persistent uncontrolled hypertension

Keywords: non-obstructive hypertrophic cardiomyopathy genetic cardiomyopathy